EP1745783A1 - Composés à base de pyrazoline, leur préparation et leur utilisation comme médicaments - Google Patents

Composés à base de pyrazoline, leur préparation et leur utilisation comme médicaments Download PDF

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EP1745783A1
EP1745783A1 EP05384028A EP05384028A EP1745783A1 EP 1745783 A1 EP1745783 A1 EP 1745783A1 EP 05384028 A EP05384028 A EP 05384028A EP 05384028 A EP05384028 A EP 05384028A EP 1745783 A1 EP1745783 A1 EP 1745783A1
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group
optionally
branched
substituted
preparation
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Helmut Heinrich Buschmann
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Esteve Pharmaceuticals SA
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Laboratorios del Dr Esteve SA
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Priority to EP05384028A priority Critical patent/EP1745783A1/fr
Priority to PCT/EP2006/006956 priority patent/WO2007009682A1/fr
Priority to PCT/EP2006/007419 priority patent/WO2007025613A2/fr
Priority to US11/991,225 priority patent/US20090325975A1/en
Publication of EP1745783A1 publication Critical patent/EP1745783A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to substituted pyrazoline compounds, methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.
  • Cannabinoids are compounds, which are derived from the cannabis sativa plant which is commonly known as marijuana.
  • the most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly ⁇ 9 -THC.
  • cannabinoids as well as their synthetic analogues promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.
  • CB 1 and CB 2 are involved in a variety of physiological or pathophysiological processes in humans and animals, e.g. processes related to the central nervous system, immune system, cardiovascular system, endocrinous system, respiratory system, the gastrointestinal tract or to reproduction, as described for example, in Hollister, Pharm. Rev. 38, 1986, 1-20 ; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991 ; Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992 .
  • the CB 1 -Receptor is involved in many different food-intake related disorders such as bulimia or obesity, including obesity associated with type II diabetes (non-insulin-dependent diabetes) and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
  • these compounds have a high affinity for cannabinoid receptors, particularly for the CB 1 -receptor, and that they act as modulators e.g. antagonists, inverse agonists or agonists on these receptors. They are therefore suitable for the prophylaxis and/or treatment of various disorders related to the central nervous system, the immune system, the cardiovascular system, the endocrinous system, the respiratory system, the gastrointestinal tract or reproduction in humans and/or animals, preferably humans including infants, children and grown-ups.
  • the present invention relates to substituted pyrazoline compounds of general formula I, wherein R 1 represents an optionally at least mono-substituted phenyl group, R 2 represents an optionally at least mono-substituted phenyl group, R 3 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an ⁇ NR 4 R 5 -moiety, R 4 and R 5 , identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substit
  • a mono- or polycyclic ring-system means a mono-or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic.
  • each of the rings of the mono- or polycyclic ring system may contain one or more, e.g. 1, 2 or 3, heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S.
  • the polycyclic ring-system may comprise two rings that are condensed.
  • the rings of the mono- or polycyclic ring-sytem are preferably 5- or 6-membered.
  • condensed means that a ring or ring-system is attached to another ring or ring-system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-6 -alkoxy, branched or unbranched C 1-6 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, oxo, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-C 1-4 -alkyl, - SO-C 1-4 -alkyl, -SO 2 -C 1-4 -alkyl, -NH-SO 2 -C 1-4 1-4
  • residues R 3 -R 8 represents or comprises a cycloaliphatic group, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of of N, O and S.
  • a cycloaliphatic group may contain 1, 2 or 3 heteratoms independently selected from the group consisting of N, O and S as ring members.
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing, optionally at least mono-substituted cycloaliphatic groups may preferably be selected from the group consisting of Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclooctenyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, homo-Piperazinyl and Morpholinyl.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-6 -alkoxy, branched or unbranched C 1-6 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, oxo, amido, cyano, nitro, -SO 2 NH 2 , -CO-C 1-4 -alkyl, -SO-C 1-4 -alkyl, -SO 2 -C 1-4 -alkyl, -NH-SO 2 -C 1-4 -alkyl , wherein the C 1-4 -alkyl
  • residues R 1 -R 8 represents or comprises an aryl group, including a phenyl group, which is substituted by one or more, e.g. 1, 2, 3, 4 or 5 substituents, unless defined otherwise, each of the substituents may be independently selected from the group consisting of a halogen atom (e.g.
  • a linear or branched C 1-6 -alkyl group a linear or branched C 1-6 alcoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-C 1-6 -alkyl group, a cyano group, a nitro group, a carboxy group, a -CO-O-C 1-6 -alkyl group, a ⁇ CO-NR A R B - moiety, a -CO-NH-NR C R D -moiety, an ⁇ SH, an -S-C 1-6 -alkyl group, an -SO-C 1 - 6 -alkyl group, an -SO 2 -C 1-6 -alkyl group, a -C 1-6 -alkylene-S-C 1-6 -alkyl group, a -C 1-6 -alkylene-SO-C 1-6
  • Preferred aryl groups which may optionally be at least mono-substituted, are phenyl and naphthyl.
  • each of the substituents may be independently selected from the group consisting of a halogen atom (e.g.
  • a linear or branched C 1-6 -alkyl group a linear or branched C 1-6 alcoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a-CO-C 1-6 -alkyl group, a cyano group, a carboxy group, a ⁇ CO-O-C 1-6 -alkyl group, a ⁇ CO-NR A R B - moiety, a -CO-NH-NR C R D -moiety, an -S-C 1-6 -alkyl group, an -SO-C 1-6 -alkyl group, an -SO 2 -C 1-6 -alkyl group, a -C 1-6 -alkylene-S-C 1-6 -alkyl group, a -C 1-6 -alkylene-SO-C 1-6 -alkyl group, a -C 1-6 -alkyl group,
  • heteroatoms which are present as ring members in the heteroaryl radical, may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulphur.
  • a heteroaryl radical may comprise 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.
  • Suitable heteroaryl groups may preferably be selected from the group consisting of thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, indolyl, chinolinyl, isochinolinyl, benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, benzo[b]furanyl, imidazo[2,1-b]thiazolyl, triazolyl, and pyrazolyl, more preferably be selected from the group consisting of thienyl-, benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, imidazo[2,1-b]thiazolyl, triazolyl and pyrazolyl.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-C 1-4 -alkyl, -SO-C 1-4 -alkyl, -SO 2 -C 1-4 -alkyl, -NH-SO 2 -C 1-4 -alkyl, wherein the C 1-4 -alkyl may in each case be
  • Preferred linear or branched, saturated or unsaturated aliphatic groups which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.
  • any of the residues R 4 -R 8 represents or comprises a linear or branched alkylene group
  • said alkylene group may preferably be selected from the group consisting of ⁇ methylene -(CH 2 )-, ethylene -(CH 2 -CH 2 )-, n-propylene -(CH 2 -CH 2 -CH 2 )- or isopropylene ⁇ (-C(CH 3 ) 2 )-.
  • substituted pyrazoline compounds of general formula I given above wherein R 1 represents an optionally at least mono-substituted phenyl group, R 2 represents an optionally at least mono-substituted phenyl group, R 3 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an -NR 4 R 5 -moiety, R 4 and R 5 , identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,
  • R 3 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an ⁇ NR 4 R 5 -moiety, preferably R 3 represents a saturated, optionally at least mono-substituted, optionally one or more nitrogen-atoms as ring member containing C 3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3
  • substituted pyrazoline compounds of general formula I given above are preferred, wherein R 4 and R 5 , identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 -aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3-8 -cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, an ⁇ SO 2 -R 6 -moiety, or
  • substituted pyrazoline compounds of general formula I given above wherein R 6 represents a linear or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 aliphatic group, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3-8 cycloaliphatic group, which may be condensed with a mono-or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl or heteroaryl group, which may be condensed with a mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, preferably R 6 represents a C 1-6 -alkyl group, a saturated, optionally at least mono-substituted cycloaliphatic group, which may be condensed with a mono-or polycycl
  • R 7 and R 8 identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C 1-6 aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C 3-8 cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or an optionally at least mono-substituted, 5- or 6 membered aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system and/or bonded via a methylene (-CH 2 -) or ethylene (-CH 2 -CH 2 )-group, preferably represent a hydrogen atom or a C 1-6 alkyl radical
  • R 1 represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position
  • R 2 represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position
  • R 3 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an ⁇ NR 4 R 5 -moiety
  • R 4 represents a hydrogen atom or a linear or branched C 1-6 -alkyl group
  • R 5 represents a linear or branched C 1-6 alkyl group
  • pyrrolidinyl group a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an ⁇ NR 4
  • substituted pyrazoline compounds selected from the group consisting of:
  • the present invention also provides a process for the preparation of substituted pyrazoline compounds of general formula I, according to which at least one benzaldehyde compound of general formula IV wherein R 1 has the meaning given above, is reacted with a pyruvate compound of general formula (V) wherein G represents an OR group with R being a branched or unbranched C 1-6 alkyl radical, preferably an ethyl radical, or G represents an O - K group with K being a cation, preferably a monovalent cation, more preferably an alkali metal cation, even more preferably a sodium cation, to yield a compound of general formula (VI) wherein R 1 has the meaning given above, which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (VII) or a corresponding salt thereof, wherein R 2 has the meaning given above, under an inert atmosphere, to yield a compound of
  • the reaction of the benzaldehyde compound of general formula IV with a pyruvate compound of general formula V is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11), 2229-33, (1996) .
  • an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide
  • sodium pyruvate may be used as the pyruvate compound.
  • said reaction is carried out in a protic reaction medium such as a C 1-4 alkyl alcohol or mixtures of these. Mixtures of such alcohols with water, e.g. ethanol/water may also be used.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 °C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours. Also preferred the reaction of the benzaldehyde compound of general formula IV with a pyruvate compound of general formula V is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(II)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001 . The respective description is hereby incorporated by reference and forms part of the disclosure.
  • reaction of the compound of general formula (VI) with an optionally substituted phenyl hydrazin of general formula (VII) is preferably carried out in a suitable reaction medium such as C 1-4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • a suitable reaction medium such as C 1-4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 °C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • the carboxylic group of the compound of general formula (VIII) may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art.
  • the compounds of general formula (VIII) are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a C 1-4 alkyl ester, an activated ester such as p-nitrophenylester.
  • Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N-oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).
  • said activated compound of general formula (IX) is an acid chloride
  • it is preferably prepared by reaction of the corresponding acid of general formula (VIII) with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent.
  • an additional solvent may be used.
  • Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane.
  • reaction temperature range from 0o C to the boiling point of the solvent and reaction times from several minutes to several hours.
  • said activated compound of general formula (IX) is a mixed anhydride
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (VIII) with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.
  • reaction of general formula (IX) with a compound of general formula HR 3 to yield compounds of general formula I, wherein R 3 represents an ⁇ NR 4 R 5 moiety is preferably carried out in presence of a base such as triethylamine in a reaction medium such as methylenchloride.
  • a base such as triethylamine
  • a reaction medium such as methylenchloride.
  • the temperature is preferably in the range from 0oC to the boiling point of the reaction medium.
  • the reaction time may vary over a broad range, e.g. from several hours to several days.
  • reaction is carried out in the presence of a Lewis acid, which is preferably selected from the group consisting of FeCl 3 , ZnCl 2 and AlCl 3 , in a suitable reaction medium such as toluene, benzene, tetrahydrofurane or similar.
  • a Lewis acid which is preferably selected from the group consisting of FeCl 3 , ZnCl 2 and AlCl 3
  • a suitable reaction medium such as toluene, benzene, tetrahydrofurane or similar.
  • the temperature is preferably in teh range from 0oC to the boiling point of the reaction medium, more preferably from 15 to 25 °C.
  • the reaction time may vary over a broad range, e.g. from several minutes to several hours.
  • the present invention relates to the compound optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof, in particular as an intermediate in a process for preparing substituted pyrazoline compounds of general formula (I).
  • the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula (I) and stereoisomers thereof, wherein at least one compound of general formula (I) having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium.
  • suitable reaction media include, for example, any of the ones given above.
  • Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g.
  • the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula (I) or stereoisomers thereof, wherein at least one compound of general formula (I) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium.
  • suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g.
  • reaction media are, for example, any of the ones given above.
  • Solvates, preferably hydrates, of the substituted pyrazoline compounds of general formula (I), of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.
  • Substituted pyrazoline compounds of general formula I which comprise nitrogen-atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art.
  • substituted pyrazoline compounds as used herein is to be understood as encompassing derivatives such as ethers, esters and complexes of these compounds as well.
  • derivatives as used in this application is defined here as meaning a chemical compound having undergone a chemical derivation starting from an acting (active) compound to change (ameliorate for pharmaceutical use) any of its physico-chemical properties, especially a so-called prodrug, e.g. their esters and ethers.
  • substituted pyrazoline compounds of general formula (I) given below are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments. It has been found that the substituted pyrazoline compounds of general formula I given below, stereoisomers thereof, N-oxides thereof, corresponding salts and corresponding solvates have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CB 1 )-receptors, i.e. they are selective ligands for the (CB 1 )-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors.
  • cannabinoid 1 (CB 1 )-receptors particularly cannabinoid 1 (CB 1 )-receptors, i.e. they are selective ligands for the (CB 1 )-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors
  • these pyrazoline compounds show little or no development of tolerance during treatment, particularly with respect to food intake, i.e. if the treatment is interrupted for a given period of time and then continued afterwards, the inventively used pyrazoline compounds will again show the desired effect. After ending the treatment with the pyrazoline compounds, the positive influence on the body weight is found to continue. Furthermore, these pyrazoline compounds show relatively weak Herg channel affinity, thus a low risk of prolongation of the QT-interval is to be expected for these compounds.
  • the inventively used pyrazoline compounds are distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient.
  • linear or branched, saturated or unsaturated aliphatic groups which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.
  • alkyl and cycloalkyl radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted.
  • C 1-2 -alkyl represents C1- or C2-alkyl
  • C 1-3 -alkyl represents C1-, C2- or C3-alkyl
  • C 1-4 -alkyl represents C1-, C2-, C3- or C4-alkyl
  • C 1-5 -alkyl represents C1-, C2-, C3-, C4-, or C5-alkyl
  • C 1-6 -alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl
  • C 1-7 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • C 1-10 -alkyl represents C1-, C2-, C3-, C4-, C5-, C
  • C 3-4 -cycloalkyl represents C3- or C4-cycloalkyl
  • C 3-5 -cycloalkyl represents C3-, C4- or C5-cycloalkyl
  • C 3-6 -cycloalkyl represents C3-, C4-, C5- or C6-cycloalkyl
  • C 3-7 -cycloalkyl represents C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3-8 -cycloalkyl represents C3-, C4-, C5-, C6-, C7- or C8-cycloalkyl
  • C 4-5 -cycloalkyl represents C4- or C5-cycloalkyl
  • C 4-6 -cycloalkyl represents C4-, C5- or C6-cycloalkyl
  • C 4-7 -cycloalkyl represents C4-, C5-, C6- or C7-cycloalkyl, C 5-6
  • cycloalkyl in respect of cycloalkyl, the term also includes saturated cycloalkyls in which one or 2 carbon atoms are replaced by a heteroatom, S, N or O.
  • mono- or polyunsaturated, preferably monounsaturated, cycloalkyls without a heteroatom in the ring also in particular fall under the term cycloalkyl as long as the cycloalkyl is not an aromatic system.
  • alkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, and also adamantyl, (if substituted also CHF 2 , CF 3 or CH 2 OH) as well as pyrazolinone, oxopyrazolinone, [1,4]
  • substituted in the context of this invention is understood as meaning replacement of at least one hydrogen radical by F, Cl, Br, I, NH 2 , SH or OH
  • Particularly preferred substituents here are F, Cl and OH.
  • the hydrogen radical can also be replaced by OC 1-3 -alkyl or C 1-3 -alkyl (in each case mono- or polysubstituted or unsubstituted), in particular methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3-6 is to be understood as meaning -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, (CH 2 ) 1-4 is to be understood as meaning -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, (CH 2 ) 4-5 is to be understood as meaning -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, etc.
  • An aryl radical is understood as meaning ring systems with at least one aromatic ring but without heteroatoms even in only one of the rings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which can be unsubstituted or monosubstituted or polysubstituted.
  • a heteroaryl radical is understood as meaning heterocyclic ring systems which have at least one unsaturated ring and can contain one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur and can also be mono- or polysubstituted.
  • heteroaryls examples which may be mentioned from the group of heteroaryls are furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole and quinazoline.
  • substituted is understood as meaning substitution of the aryl or heteroaryl by R, OR, a halogen, preferably F and/or Cl, a CF 3 , a CN, an NO 2 , an NRR, a C 1-6 -alkyl (saturated), a C 1-6- alkoxy, a C 3-8 -cycloalkoxy, a C 3-8 -cycloalkyl or a C 2-6 -alkylene.
  • R 2' , R 3' or R 4' represents hydrogen, while at least one of R 2' , R 3' or R 4' is different from hydrogen.
  • R 7' represents hydrogen.
  • R 2' , R 3' and R 4' independently of each other represent hydrogen, a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 2' , R 3' and R 4' independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 5' and R 6' independently of each other represent a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 5' and R 6' independently of each other represent methyl, ethyl, F, Cl, Br and CF 3 .
  • R 2' represents a chlorine atom in the 4-position of the phenyl ring
  • R 3' and R 4' represent hydrogen
  • R 5' and R 6' each represent a chlorine atoms in the 2- and 4-position of the phenyl ring
  • R 7' represents hydrogen
  • R 1' represents hydrogen, methyl or ethyl, preferably hydrogen.
  • the compound of general formula II is represented by a compound of general formula III wherein R 1' represents hydrogen or a linear or branched C 1-4 -alkyl group, R 12 or R 13 independently of each other represent a linear or branched C 1-6 -alkyl group, a linear or branched C 1-6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH, NH 2 , hydrogen, methyl, ethyl, F, Cl, Br and CF 3 , R 14 or R 15 independently of each other represent a linear or branched C 1-6 -alkyl group, a linear or branched C 1-6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH, NH 2 , methyl, ethyl, F, Cl, Br and CF III
  • R 1' represents hydrogen
  • R 12 and R 13 independently of each other represent hydrogen, a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 14 , and R 15 independently of each other represent a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent methyl, ethyl, F, Cl, Br and CF 3 .
  • R 13 represents Cl and R 12 represents hydrogen.
  • R 14 and R 15 each represent Cl.
  • R 1' represents hydrogen, methyl or ethyl, preferably hydrogen.
  • the compound according to formula II or III is selected from the group consisting of:
  • the present invention also provides a process for the preparation of substituted pyrazoline compounds of general formula II or III, wherein R 1' is hydrogen, given above, in that at least one benzaldehyde compound of general formula IV' wherein R 2' , R 3' and R 4' have the meaning mentioned above, is reacted with a pyruvate compound of general formula (V') wherein G represents an OR group with R being a branched or unbranched C 1-6 alkyl radical or G represents an O - K group with K being a cation, preferably an anorganic kation, more preferably an alkali metal kation, most preferably sodium, to yield a compound of general formula (VI') which is optionally isolated and/or optionally purified, and which is reacted with an optionally substituted phenyl hydrazine of general formula (VII') or a corresponding salt thereof, wherein R 5' , R 6' and R 7' have the meaning mentioned above, under inert
  • the inventive process is also illustrated in scheme I given below:
  • the reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula V' is preferably carried out in the presence of at least one base, more preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic communications, 26(11), 2229-33, (1996) .
  • the respective description is hereby incorporated by reference and forms part of the disclosure.
  • Preferably said reaction is carried out in a protic reaction medium such as a C 1-4 alkyl alcohol or mixtures of these.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range.
  • Preferred reaction temperatures range from -10°C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • reaction of the benzaldehyde compound of general formula III with a pyruvate compound of general formula V' is carried out under acid catalysed conditions, more preferably by refluxing the mixture in dichloromethane in the presence of copper(II)trifluoromethanesulfonate as described, for example, in Synlett, (1), 147-149, 2001 .
  • the respective description is hereby incorporated by reference and forms part of the disclosure.
  • reaction of the compound of general formula (VI') with an optionally substituted phenyl hydrazin of general formula (VII') is preferably carried out in a suitable reaction medium such as C 1-4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • a suitable reaction medium such as C 1-4 -alcohols or ethers such as dioxane or tetrahydrofurane or mixtures of at least two of these afore mentioned compounds.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, or a mixture of at least two of these bases may also be used.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 °C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • the carboxylic group of the compound of general formula (VIII') may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art.
  • the compounds of general formula (VIII') are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a C 1-4 alkyl ester, an activated ester such as p-nitrophenylester.
  • Other well known methods for the activation of acids include the activation with N,N-dicyclohexylcarbodiimide or benzotriazol-N-oxotris(dimethylamino) phosphonium hexafluorophosphate (BOP)).
  • said activated compound of general formula (VIII') is an acid chloride
  • it is preferably prepared by reaction of the corresponding acid of general formula (Vlll') with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the solvent.
  • an additional solvent may be used.
  • Suitable solvents include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures of two or more solvents from one class or two or more solvents from different classes may also be used.
  • Preferred reaction temperature range from 0o C to the boiling point of the solvent and reaction times from several minutes to several hours.
  • said activated compound of general formula (VIII') is a mixed anhydride
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula (VIII') with ethyl chloroformiate in the presence of a base such as triethylamine or pyridine, in a suitable solvent.
  • the activated compound can be reacted with an alkyl-alcohol to arrive at compounds according to general formulas II or III with R 1' being a a linear or branched C 1-4 -alkyl group.
  • substituted pyrazoline compounds of general formula II or III themselves are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or fractionalized crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
  • the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula II or III and stereoisomers thereof, wherein at least one compound of general formula II or III having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium.
  • suitable reaction media include, for example, any of the ones given above.
  • Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid
  • suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.
  • the present invention also provides a process for the preparation of salts of substituted pyrazoline compounds of general formula II or III or stereoisomers thereof, wherein at least one compound of general formula II or III having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium.
  • suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH n R 4-n ] + , wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched C 1-4 -alkyl-radical.
  • Suitable reaction media are, for example, any of the ones given above.
  • Solvates preferably hydrates, of the substituted pyrazoline compounds of general formula II or III, of corresponding stereoisomers, of corresponding N-oxides or of corresponding salts thereof may also be obtained by standard procedures known to those skilled in the art.
  • Substituted pyrazoline compounds of general formula II or III which comprise nitrogen-atom containing saturated, unsaturated or aromatic rings may also be obtained in the form of their N-oxides by methods well known to those skilled in the art.
  • an other aspect of the present invention relates to a medicament comprising at least one substituted pyrazoline compound of general formula I, wherein R 1 represents an optionally at least mono-substituted phenyl group, R 2 represents an optionally at least mono-substituted phenyl group, R 3 represents a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an optionally at least mono-substituted aryl or heteroaryl group, which may be condensed with an optionally at least mono-substituted mono- or polycyclic ring system, or R 3 represents an -NR 4 R 5 -moiety, R 4 and R 5 , identical or different, represent a hydrogen atom, an unbranched or branched, saturated or unsaturated, optionally
  • a mono- or polycyclic ring-system means a mono-or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or polycyclic ring system may contain one or more, e.g. 1, 2 or 3, heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S.
  • the polycyclic ring-system may comprise two rings that are condensed.
  • the rings of the mono- or polycyclic ring-sytem are preferably 5- or 6-membered.
  • condensed according to the present invention means that a ring or ring-system is attached to another ring or ring-system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-6 -alkoxy, branched or unbranched C 1-6 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, oxo, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-C 1-4 -alkyl, - SO-C 1-4 -alkyl, -SO 2 -C 1-4 -alkyl, -NH-SO 2 -C 1-4 1-4
  • residues R 3 -R 8 represents or comprises a cycloaliphatic group, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of of N, O and S.
  • a cycloaliphatic group may contain 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing, optionally at least mono-substituted cycloaliphatic groups may preferably be selected from the group consisting of Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclooctenyl, Pyrrolidinyl, Piperidinyl, Piperazinyl, homo-Piperazinyl and Morpholinyl.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-6 -alkoxy, branched or unbranched C 1-6 -alkyl, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -pertluoroalkyl, amino, carboxy, oxo, amido, cyano, nitro, -SO 2 NH 2 , -CO-C 1-4 -alkyl, -SO-C 1-4 -alkyl, -SO 2 -C 1-4 -alkyl, -NH-SO 2 -C 1-4 -alkyl , wherein the C 1-4 -alkyl
  • each of the substituents may be independently selected from the group consisting of a halogen atom (F, Cl, Br, I), a linear or branched C 1-6 -alkyl group, a linear or branched C 1-6 alcoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-C 1-6 -alkyl group, a cyano group, a nitro group, a carboxy group, a ⁇ CO-O-C 1-6 -alkyl group, a ⁇ CO-NR A R B -moiety, a -CO-NH-NR C R D -moiety, an ⁇ SH, an -S-C
  • Preferred aryl groups which may optionally be at least mono-substituted, are phenyl and naphthyl.
  • each of the substituents may be independently selected from the group consisting of a halogen atom (e.g.
  • a linear or branched C 1-6 -alkyl group a linear or branched C 1-6 alcoxy group, a formyl group, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, a -CO-C 1-6 -alkyl group, a cyano group, a carboxy group, a ⁇ CO-O-C 1-6 -alkyl group, a ⁇ CO-NR A R B - moiety, a -CO-NH-NR C R D -moiety, an -S-C 1-6 -alkyl group, an -SO-C 1-6 -alkyl group, an -SO 2 -C 1-6 -alkyl group, a -C 1-6 -alkylene-S-C 1-6 -alkyl group, a -C 1-6 -alkylene-SO-C 1-6 -alkyl group, a -C -C -alkylene-
  • heteroatoms which are present as ring members in the heteroaryl radical, may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulphur.
  • a heteroaryl radical may comprise 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S as ring members.
  • Suitable heteroaryl groups may preferably be selected from the group consisting of thienyl, furyl, pyrrolyl, pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, indolyl, chinolinyl, isochinolinyl, benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, benzo[b]furanyl, imidazo[2,1-b]thiazolyl, triazolyl, and pyrazolyl, more preferably be selected from the group consisting of thienyl-, benzo[1,2,5]-thiodiazolyl, benzo[b]thiophenyl, imidazo[2,1-b]thiazolyl, triazolyl and pyrazolyl.
  • each of the substituents may be independently selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C 1-4 -alkoxy, branched or unbranched C 1-4 -perfluoroalkoxy, branched or unbranched C 1-4 -perfluoroalkyl, amino, carboxy, amido, cyano, nitro, -SO 2 NH 2 , -CO-C 1-4 -alkyl, -SO-C 1-4 -alkyl, -SO 2 -C 1-4 -alkyl, -NH-SO 2 -C 1-4 -alkyl , wherein the C 1-4 -alkyl may in each case be
  • Preferred linear or branched, saturated or unsaturated aliphatic groups which may be substituted by one or more substituents, may preferably be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and butinyl.
  • any of the residues R 4 -R 8 represents or comprises a linear or branched alkylene group
  • said alkylene group may preferably be selected from the group consisting of ⁇ methylene -(CH 2 )-, ethylene -(CH 2 -CH 2 )-, n-propylene -(CH 2 -CH 2 -CH 2 )- or iso-proylene ⁇ (-C(CH 3 ) 2 )-.
  • a medicament which comprises at least one compound of general formula I given below, wherein R 1 represents a phenyl ring, which is mono-substituted with a halogen atom, preferably a chlorine atom, in its 4-position, R 2 represents a phenyl ring, which is di-substituted with two halogen atoms, preferably chlorine atoms, in its 2- and 4-position, R 3 represents a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperazinyl group, a morpholinyl group, or an -NR 4 R 5 -moiety, R 4 represents a hydrogen atom or a linear or branched C 1-6 -alkyl group, R 5 represents a linear or branched C 1-6 alkyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a homo-piperaz
  • a medicament comprising at least one substituted pyrazoline compound selected from the group consisting of:
  • the inventive medicament may preferably also comprise any of the inventive pyrazoline compounds or combinations of at least two of these pyrazoline compounds given above.
  • Said medicament may also comprise any combination of one or more of the substituted pyrazoline compounds of general formula I given above, stereoisomers thereof, corresponding N-oxides thereof, physiologically acceptable salts thereof or physiologically acceptable solvates thereof.
  • said medicament is suitable for the modulation (regulation) of cannabinoid-receptors, preferably cannabinoid 1 (CB 1 ) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • cannabinoid-receptors preferably cannabinoid 1 (CB 1 ) receptors
  • Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of psychosis.
  • said medicament is suitable for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type II diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
  • the inventive medicament also seems to be active in the prophylaxis and/or treatment of appetency disorders, e.g. the pyrazoline compounds of general formula I also reduce the desire for sweets.
  • said medicament is suitable for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
  • cancer preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
  • Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
  • Medicaments and/or drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • the medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget's disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheric neuropathy, inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhea, asthma, memory disorders,
  • Another aspect of the present invention is the use of at least one substituted pyrazoline compound of general formula I given above as suitable active substances, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CB 1 ) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • CB 1 cannabinoid 1
  • At least one of the respective pyrazoline compounds optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
  • At least one of the respective pyrazoline compounds optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type II diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
  • pyrazoline compounds optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or
  • At least one of the respective pyrazoline compounds optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
  • Medicaments/drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • At least one of the respective pyrazoline compounds optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g.
  • the medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
  • the composition of the medicament may vary depending on the route of administration.
  • the medicament of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
  • Another aspect of the present invention relates to a Medicament comprising at least one substituted pyrazoline compound of general formula II or III according to the invention and optionally one or more pharmaceutically acceptable excipients.
  • At least one of R 5' , R 6' or R 7' represents hydrogen, while at least one R 5' , R 6' or R 7' is different from hydrogen.
  • R 2' , R 3' and R 4' independently of each other represent hydrogen, a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 2' , R 3' and R 4' independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 5' , R 6' and R 7' independently of each other represent hydrogen, a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 5' , R 6' and R 7' independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 2' represents a chlorine atom in the 4-position of the phenyl ring, while R 3' and R 4' represent hydrogen.
  • R 5' and R 6' each represent a chlorine atoms in the 2- and 4-position of the phenyl ring, while R 7' represents hydrogen.
  • R 1' represents hydrogen, methyl or ethyl, preferably hydrogen.
  • the compound according to formula II is represented by a compound of general formula (III) wherein R 1' represents hydrogen or a linear or branched C 1-4 -alkyl group, R 12 , R 13 , R 14 or R 15 independently of each other represent a linear or branched C 1-6 -alkyl group, a linear or branched C 1-6 -alkoxy group, a halogen atom, CH 2 F, CHF 2 , CF 3 , CN, OH, NO 2 , SH, NH 2 , hydrogen, methyl, ethyl, F, Cl, Br and CF 3 , optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding N-oxide thereof, or a corresponding salt thereof,
  • R 12 and R 13 independently of each other represent hydrogen, a linear or branchedC 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 12 and R 13 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 14 , and R 15 independently of each other represent hydrogen, a linear or branched C 1-6 -alkyl group, a halogen atom, or CF 3 , preferably R 14 and R 15 independently of each other represent hydrogen, methyl, ethyl, F, Cl, Br and CF 3 .
  • R 13 represents Cl and R 12 represents hydrogen.
  • R 14 and R 15 each represent Cl.
  • R 1' represents hydrogen, methyl or ethyl, preferably hydrogen.
  • Another aspect of the invention is a medicament comprising at least one combination of compounds according to the invention and optionally one or more pharmaceutically acceptable excipients.
  • the medicament is for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • the medicament is for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • the medicament is for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CB 1 ) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • CBD 1 cannabinoid 1
  • the medicament is for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
  • food intake disorders preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
  • the medicament is for the prophylaxis and/or treatment of psychosis.
  • the medicament is for the prophylaxis and/or treatment of alcohol abuse and/or addiction, nicotine abuse and/or addiction, drug abuse and/or addiction and/or medicament abuse and/or addiction, preferably drug abuse and/or addiction and/or nicotine abuse and/or addiction.
  • the medicament is for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin camcer, colon cancer, bowl cancer and prostate
  • Said medicaments may also comprise any combination of one or more of the substituted pyrazoline compounds of general formula I given above, stereoisomers thereof, corresponding N-oxides thereof, physiologically acceptable salts thereof or physiologically acceptable solvates thereof.
  • medicaments are suitable for the prophylaxis and/or treatment of alcohol abuse, drug abuse and/or medicament abuse, preferably drug abuse and the treatment of obesity.
  • Medicaments and/or drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • the medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
  • the composition of the medicament may vary depending on the route of administration.
  • the medicament of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
  • Solid oral compositions (which are preferred as are liquid ones) may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to the methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form.
  • These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, multiparticles, capsules, lozenges, caplets, aqueous or oily solutions, suspensions, emulsions, gels, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate, controlled or retarded release.
  • liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
  • Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • compositions of the present invention may also be administered topically or via a suppository.
  • the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
  • the daily dosage for humans may preferably be in the range from1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula II or III according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the regulation of triglyceride levels in the blood plasma and for the prophylaxis and/or treatment of disorders of the central nervous system, especially stroke, of disorders of the cardiovascular system and of food intake disorders, especially bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity and diabetis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formaula II or III according to the invention (and optionally one or more pharmaceutically acceptable excipients,) for the preparation of a medicament for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • Another preferred aspect of the invention is the use of at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients,) for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CB 1 ) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • CBD 1 cannabinoid 1
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula II or III according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type II diabetus mellitus (non-insuline dependent diabetes mellitus), preferably obesity.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula II or III according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula II or III according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of alcohol abuse and/or addiction, nicotine abuse and/or addiction, medicament abuse and/or addiction and/or drug abuse and/or addiction, preferably drug abuse and/or addiction or nicotine abuse and/or addiction.
  • Another preferred aspect of the invention is the use of at least one substituted pyrazoline compound of formula II or III according to the invention or at least one combination of compounds according to the invention (and optionally one or more pharmaceutically acceptable excipients), for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheric neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders; bone disorders including osteoporosis or Paget's disease of bone; cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
  • the pharmaceutical excipients which can be used for the pharmaceutical composition according to the present invention include especially a diluent, a binder and a lubricant.
  • a flowing agent, an antiadhesive and, optionally, a coloring agent and/or a flavoring agent can also be added.
  • sodium alkylsulfate is understood as meaning a sodium (C8-C12)alkylsulfate, for example sodium octylsulfate or, preferably, sodium laurylsulfate.
  • the diluent used in the composition of the present invention can be one or more compounds which are capable of densifying the active principle to give the desired mass.
  • the preferred diluents are inorganic phosphates such as calcium phosphates; sugars such as hydrated or anhydrous lactose, or mannitol; and cellulose or cellulose derivatives such as, for example, microcrystalline cellulose, starch, corn starch or pregelatinized starch. Lactose monohydrate, mannitol, microcrystalline cellulose and corn starch, used by themselves or in a mixture, for example a mixture of lactose monohydrate and corn starch, are very particularly preferred.
  • the binder employed in the composition of the present invention can be one or more compounds which are capable of densifying a compound of formula (I) by converting it to larger and denser particles with better flow properties.
  • the preferred binders are alginic acid or sodium alginate; cellulose and cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or methyl cellulose; gelatin; acrylic acid polymers; and povidone, for example povidone K 30, which is a very particularly preferred binder.
  • the binder is present in a proportion of 1% to 10% by weight in the pharmaceutical composition according to the invention.
  • the lubricant employed in the composition of the present invention can be one or more compounds which are capable of preventing the problems associated with the preparation of dry forms, such as the sticking and/or seizing problems which occur in the machines during compression or filling.
  • the preferred lubricants are fatty acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium laurylsulfate, sodium stearylfumarate, zinc stearate or stearic acid; hydrogenated vegetable oils, for example hydrogenated castor oil; polyalkylene glycols, especially polyethylene glycol; sodium benzoate; or talcum.
  • Magnesium stearate is preferred according to the present invention.
  • the lubricant is present in a proportion of 0.2% to 5% by weight in the pharmaceutical composition according to the invention.
  • the antiadhesive which may be employed in the composition of the present invention can be one or more compounds which are capable of reducing the sticky character of the formulation, for example of preventing adhesion to metal surfaces.
  • the preferred antiadhesives are compounds containing silicon, for example silica or talcum.
  • the antiadhesive can be present in a proportion of 0 to 5% by weight in the pharmaceutical composition according to the invention.
  • the flowing agent which may be employed in the composition of the present invention can be one or more compounds which are capable of facilitating the flow of the prepared formulation.
  • the preferred flowing agents are compounds containing silicon, for example anhydrous colloidal silica or precipitated silica.
  • the flowing agent can be present in a proportion of 0 to 15% by weight in the pharmaceutical composition according to the invention.
  • the disintegrating agent is understood as meaning cellulose or cellulose derivatives such as sodium carboxymethyl cellulose or crosslinked sodium carboxymethyl cellulose, crospovidone, pregelatinized starch or sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose being a preferred disintegrating agent.
  • the pharmaceutical compositions may be prepared by a wet granulation or by a layering process.
  • the internal phase, the active principle, the diluent, the binder, the disintegrating agent, the sodium alkylsulfate and, optionally, the coloring agent are mixed at room temperature and then wetted with the granulating liquid.
  • the wet mass obtained is dried and then graded.
  • the ingredient or ingredients of the external phase namely the lubricant, possibly the antiadhesive, the flowing agent and, if appropriate, the coloring agent and/or the flavoring agent, are then added to the graded dry grains.
  • the layering process is characterized in that to an inert sugar/starch spherical core, a first layer is applied containing a mixture of the active ingredient, the diluent, the binder, the disintegrating agent, the sodium alkylsulfate and, optionally, the coloring agent, optionally followed by a second isolation layer formed by water soluble polymers and compatible excipients. Finally, a layer consisting of an enteric coating is applied.
  • the inventors of the present invention also discovered that the release of a drug in the colon, which is low in water content, can be achieved by providing a preparation adapted to absorb water into its core to undergo substantially complete gelation during its stay in the upper digestive tract such as stomach and small intestine, and then move in the form of the gel down to the lower digestive tract.
  • the present invention was achieved based on the above finding.
  • another aspect of the present invention relates to a hydrogel-type sustained-release preparation
  • a hydrogel-type sustained-release preparation comprising (1) at least one drug, (2) an additive providing for a penetration of water into the core of the preparation, and (3) a hydrogel-forming polymer, which preparation undergoes a substantially complete gelation during its stay in the upper digestive tract such as stomach and small intestine and is capable of releasing a drug in the colon.
  • substantially complete gelation of the preparation refers to the state in which not less than about 70%, preferably not less than about 80%, of the preparation is gelled.
  • the sustained-release preparation of the present invention prolongs the absorption period of the drug to a remarkable extent and, hence, insures a steady blood level of the drug.
  • the preparation of the present invention absorbs water during its stay in the upper digestive tract to undergo a substantially complete gelation and then moves down into the lower digestive tract with its surface being constantly eroded, and maintains drug release by further erosion in the lower digestive tract, with the result that a sustained and sufficient absorption of the drug is achieved even in the colon where little water is available.
  • sustained-release preparation of the present invention is described in further detail hereinafter.
  • the drug or drugs which can be used in the preparation according to the present invention are not particularly limited in kind, provided that they are used for sustained-release system.
  • polyoxyethylene-hydrogenated castor oils polyoxy-ethylene-sorbitan higher fatty acid esters, polyoxyethylene polyoxypropylene glycols, sucrose fatty acid esters, etc.
  • a solubilizer such as a polymer (e.g., a water-soluble polymer such as hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), etc.
  • HPMC hydroxypropylmethylcellulose
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • CMEC carboxymethylethylcellulose
  • HPMCP hydroxypropylmethylcellulose phthalate
  • Eudragit L and S the trade name of Rhom & Haas Co.
  • the method comprising adding an organic acid such as citric acid, tartaric acid or the like can be employed.
  • the method involving the formation of a soluble salt or the method comprising forming a clathrate using cyclodextrin or the like can also be employed. These procedures for solubilization can be modified as necessary according to the particular drug.
  • hydrophilic base The additive for allowing water to penetrate into the core of the preparation according to the present invention (this additive for insuring a penetration of water into the preparation core will hereinafter be referred to as "hydrophilic base”) is such that the amount of water required to dissolve 1 g of the hydrophilic base is not more than 5 ml and preferably not more than 4 ml at the temperature of 20 +/- 5 DEG C.
  • the hydrophilic base includes, inter alia, highly hydrophilic polymers such as polyethylene glycol (PEG; e.g.
  • HCO polyoxyethylene-hydrogenated castor oil
  • Cremophor RH40 produced by BASF, HCO-40 and HCO-60 produced by Nikko Chemicals Co.
  • polyoxyethylene-polyoxypropylene glycol e.g. Pluronic F68 produced by Asahi Denka Kogyo K.K.
  • polyoxyethylene-sorbitan high molecular fatty acid ester Teween; e.g. Tween 80 produced by Kanto Kagaku K.K.
  • salts such as sodium chloride, magnesium chloride, etc., organic acids such as citric acid, tartaric acid, etc.
  • amino acids such as glycine, beta -alanine, lysine hydrochloride, etc.
  • amino sugars such as meglumine.
  • Preferred ones are PEG6000, PVP, D-sorbitol, etc.
  • the proportion of such hydrophilic base depends on the characteristics of the drug (solubility, therapeutic efficacy, etc.) and content of the drug, solubility of the hydrophilic base itself, characteristics of the hydrogel-forming polymer used, the patient's condition at the time of administration and other factors. However, the proportion may preferably be a sufficient level to achieve a substantially complete gelation during the stay of the preparation in the upper digestive tract.
  • the preparation stays in the upper digestive tract in a different period depending on the species and the individual but in about 2 hours after administration in the case of dogs and in about 4 to 5 hours after administration in the case of human ( Br. J. clin.
  • the proportion may preferably be a sufficient level to achieve a substantially complete gelation in about 4 to 5 hours after administration.
  • the proportion of the hydrophilic base is, therefore, generally about 5-80% by weight and preferably about 5-60% by weight based on the total weight of the preparation.
  • the content of the hydrophilic base When the content of the hydrophilic base is too small, the necessary gelation into the core of the preparation does not proceed so that the release of the drug in the colon becomes insufficient. On the other hand, when the content of the hydrophilic base is excessive, the gelation proceeds in a shorter time but the resulting gel becomes so fragile that the release of the drug is too fast, thus failing to insure a sufficient sustained release. Moreover, because the amount of the base is large, the product becomes bulky.
  • the hydrogel-forming polymer mentioned above should have the physical characteristics, inclusive of viscosity in the gelled state, which permit the preparation of the present invention to retain its shape more or less during its travel down to the lower digestive tract, namely the colon, by withstanding the contractile forces of the digestive tract associated with the digestion of food.
  • the hydrogel-forming polymer which can be used in the preparation of the present invention is preferably a polymer showing a high viscosity on gelation.
  • a polymer showing a viscosity of not less than 1000 cps in 1% aqueous solution (at 25 DEG C) is particularly preferred.
  • the properties of the polymer depend on its molecular weight.
  • the hydrogel-forming polymer which can be used in the present invention is preferably a substance of comparatively high molecular weight, viz. a polymer having an average molecular weight of not less than 2 x 10 ⁇ 6> and more preferably not less than 4 x 10 ⁇ 6>.
  • polyethylene oxide (PEO) having a molecular weight of not less than 2 x 10 ⁇ 6> e.g., Polyox WSR-303 (average mol. wt.: 7 x 10 ⁇ 6>; viscosity: 7500-10000 cps, 1% in H2O, 25 DEG C), Polyox WSR Coagulant (average mol. wt.: 5 x 10 ⁇ 6>; viscosity: 5500-7500 cps, under the same condition above), Polyox WSR-301 (average mol.
  • PEO polyethylene oxide
  • HEC Daicel SE900 (average mol. wt.: 156 x 10 ⁇ 4>; viscosity: 4000-5000 cps, under the same condition above), all of which are trade names of Daicel Chemical Industries]; carboxyvinyl polymers [e.g., Carbopol 940 (average mol. wt.: ca. 25 x 10 ⁇ 5>; B.F.Goodrich Chemical Co.) and so on.
  • the preferred is a PEO having an average molecular weight of not less than 2 x 10 ⁇ 6>.
  • a polymer having a higher molecular weight preferably an average molecular weight of not less than 4 x 10 ⁇ 6>, or a higher viscosity, preferably a viscosity of not less than 3000 cps at a concentration of 1% in water at 25 DEG C, is preferable.
  • the above hydrogel-forming polymer may be used singly, or two or more kind(s) of the above hydrogel-forming polymers in mixture may be used. Or, the mixture of two or more kinds of any polymers, which mixture has characteristics suitable for the present invention, may be suitably used for the present invention.
  • the preparation contains 10-95 weight % (preferably, 15-90 weight %) of the hydrogel-forming polymer based upon the preparation weighing less than 600 mg, and one preparation contains not less than 70 mg per preparation and preferably not less than 100 mg per preparation of the hydrogel-forming polymer. If the amount of this polymer is less than the above-mentioned level, the preparation will not tolerate erosion in the digestive tract for a sufficiently long time and a sufficient sustained release may not be achieved.
  • hydrophilic base and hydrogel-forming polymer (the latter is hereinafter referred to as hydrogel-forming base), their usefulness has been established by the following experiments.
  • liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
  • Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • compositions of the present invention may also be administered topically or via a suppository.
  • the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
  • the daily dosage for humans may preferably be in the range from1 to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
  • Substances with affinity for cannabinoid receptors are known to produce a wide range of pharmacological effects. It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice produces analgesia , hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has affinity for cannabinoid-receptors, since all of these effects are common for various classes of centrally active agents. However, substances, which show all of these effects, i.e. substances that are active in this so-called tetrad model are considered to have affinity for the cannabinoid receptors. It has further been shown that cannabinoid receptor antagonists are higly effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.
  • mice with a weight of 20-30 g Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) are used in all of the following experiments.
  • mice are acclimatized to the experimental setting.
  • Pre-Treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
  • mice In order to determine the agonistic activty of the substance to be tested, the mice are injected intravenously with the substance to be tested or the vehicle alone. 15 minutes after injection, latency in hot plate analgesia is measured. Rectal temperature, sedation and catalepsy are measured 20 minutes after injection.
  • the hot plate analgesia is determined according to the method described in Woolfe D. et al. "The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944 . The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • mice are placed on a hot plate (Harvard Analgesimeter) at 55 ⁇ 0.5 °C until they show a painful sensation by licking their paws or jumping and the time for these sensations to occur is recorded. This reading is considered the basal value (B).
  • B basal value
  • PC cut-off time
  • mice Fifteen minuts after the administration of the substance to be tested, the mice are again placed on the hot plate and the afore described procedure is repeated. This period is called the post-treatment reading (PT).
  • PT post-treatment reading
  • Sedation and ataxia is determined according to the method described in Desmet L. K. C. et al. "Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975 .
  • the respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the chosen scoring system is
  • the base-line rectal temperatures are determined with a thermometer (Yello Springs Instruments Co., Panlabs) and a thermistor probe inserted to 25mm before the administration of the substance to be tested. Rectal temperature is again measured 20 minutes after the administration of the substances to be tested. The temperature difference is calculated for each animal, whereby differences of ⁇ -2 oC are considered to represent activity.
  • Catalepsy is determined according to the method described in Alpermann H. G. et al. "Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992 . The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the cataleptic effect of the substance to be tested is evaluated according to the duration of catalepsy, whereby the animals are placed head downwards with their kinlegs upon the top of the wooden block.
  • the chosen scoring system is:
  • N-piperidinyl-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide 1 mg corn starch 51 mg 200 mesh lactose monohydrate 103.33mg povidone K 30 4.3mg crosslinked sodium carboxymethyl cellulose 8.5mg
  • the spheres are dried before applying the second layer.
  • 350 g of deionized water 52 g of hydroxypropylmethylcellulose and 7 g of titanium dioxide are dispersed and the resulting aqueous dispersion is sprayed on the spheres obtained in the previous step. After spraying, the spheres are dried before applying the third enteric coating layer.
  • CPTA and TC-5E were dissolved in a solvent mixture (dichloromethane-methanol) and using a Hi-Coater, this immediate-release component (QR; CPTA: 15 mg) was coated on the SR (CPTA: 65 mg) component to provide tablets each weighing 194.1 mg (CPTA: 80 mg).
  • step a) (12.6 g, 60 mmoles), 2,4-dichlorophenylhydrazine hydrochloride (12.8 g, 60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 °C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield).
  • N-aminopiperidine (0.6 mL, 5.6 mmoles) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL).
  • methylene chloride 25 mL
  • the resulting mixture was ice-cooled down to 0°C and a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride obtained in step (c) in methylene chloride (15 mL) was added dropwise.
  • the resulting reaction mixture was stirred at room temperature (approximately 25 °C) overnight.
  • Example 12 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid-[1,2,4]triazol-4-yl amide
  • N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0,15 g, 332 mmoles) was dissolved in 7 ml of dichloromethane. The resulting solution was ice-cooled to 0 °C and m-chloroperbenzoic acid (0,204 g, 0,83 mmoles) added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was remaining. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered.
  • Table II Compound according to example: dosis administered: 5 mg/kg i.v. Agonistic effect dosis administered 5 mg/kg i.v. prior to Win 55212-2 in a dose of 1,25mg/kg i.v. Antagonistic Effect A B C. D A B. C D 1 0 0 0 0 74 100 100 100 5 0 50 0 0 50 40 20 20 i.v. intravenous A: Hot-Plate test B: Hypothermia C: Catalepsy D: Sedation
  • inventive pyrazoline compounds show an antagonistic effect.
  • the second group of rats was treated with the inventive compound N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide according to Example 1. Said compound was administered intraperitoneally to the rats over a period of 14 days in a daily dosis of (10 mg/kg body weight).
  • the third group of rats was treated with Amphetamine, an active ingredient known to reduce appetite. Said compound was administered intraperitoneally to the rats over a period of 14 days in a daily dosis of (5 mg/kg body weight).
  • Figure 2 shows the reduction of food intake due to the administration of the inventive compound according to example 11.

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EP05384028A 2005-07-15 2005-07-15 Composés à base de pyrazoline, leur préparation et leur utilisation comme médicaments Withdrawn EP1745783A1 (fr)

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EP05384028A EP1745783A1 (fr) 2005-07-15 2005-07-15 Composés à base de pyrazoline, leur préparation et leur utilisation comme médicaments
PCT/EP2006/006956 WO2007009682A1 (fr) 2005-07-15 2006-07-15 Formulations pharmaceutiques orales comprenant des composes de pyrazoline substitues
PCT/EP2006/007419 WO2007025613A2 (fr) 2005-07-15 2006-07-27 Utilisation de composes se liant au recepteur sigma pour traiter la douleur associee au diabete
US11/991,225 US20090325975A1 (en) 2005-07-15 2006-07-27 Use of compounds binding to the sigma receptor for the treatment of diabetes-associated pain

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EP1967181A1 (fr) * 2007-03-06 2008-09-10 Laboratorios del Dr. Esteve S.A. Formulation pharmaceutique comprenant un composé récepteur CB1 dans une solution solide et/ou une dispersion solide

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
EP1967181A1 (fr) * 2007-03-06 2008-09-10 Laboratorios del Dr. Esteve S.A. Formulation pharmaceutique comprenant un composé récepteur CB1 dans une solution solide et/ou une dispersion solide
WO2008107179A1 (fr) * 2007-03-06 2008-09-12 Laboratorios Del Dr. Esteve, S.A. Formulation pharmaceutique comprenant un composé récepteur de cb1 dans une solution solide et/ou une dispersion solide
ES2347633A1 (es) * 2007-03-06 2010-11-02 Laboratorios Del Dr. Esteve, S.A. Formulacion farmaceutica que comprende un compuesto receptor cb1 en una solucion solida y/o dispersion solida.

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